Xenotransplanted Human Cortical Neurons Reveal Species-Specific Development and Functional Integration into Mouse Visual Circuits

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here, we investigate human cortical neuron development, plasticity, and function using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging of the transplanted cells reveal a coordinated developmental roadmap recapitulating key milestones of human cortical neuron development. The human neurons display a prolonged developmental timeline, indicating the neuron-intrinsic retention of juvenile properties as an important component of human brain neoteny. Following maturation, human neurons in the visual cortex display tuned, decorrelated responses to visual stimuli, like mouse neurons, demonstrating their capacity for physiological synaptic integration in host cortical circuits. These findings provide new insights into human neuronal development and open novel avenues for the study of human neuronal function and disease. [Display omitted] [Display omitted] •Cell-intrinsic mechanisms of human neoteny in mouse-human chimeric cerebral cortex•Human neurons show prolonged maturation and single-cell integration in mouse cortex•Stable dendritic spines and long-term synaptic plasticity in xenotransplanted neurons•Human neurons show decorrelated activity and tuned responses to visual stimuli Human cortical neurons integrate as single cells in the mouse cortex and display human-like prolonged development, indicating cell-intrinsic mechanisms. Following maturation in the visual cortex, xenotransplanted human neurons display decorrelated activity and tuned responses to visual stimuli that are similar to host neurons.